JOURNAL OF
MEDICINAL CHEMISTRY 0 Copyright 1992 by the American Chemical Society
Volume 36, Number 19
September 18, 1992
Synthesis and Antimalarial Properties of 1-Imino Derivatives of 7-Chloro-3-substituted-3,4-dihydro-1,9(21FI,1O~)-acridinediones and Related Stephen J. Kesten, Margaret J. Degnan, Jocelyn Hung,Dennis J. McNamara, Daniel F. Ortwine, Susan E. Uhlendorf, and Leslie M. Werbel* Warner-LambertlParke-DavisPharmaceutical Research, Ann Arbor, Michigan 48105. Received June 3,1992 To improve upon the activity and properties of the 3-aryl-7-chloro-3,4dihydro-l,9(W,10H)-acrid~edionea, a variety of 1-[(alkylamino)alkylene]iminoderivatives (3) were prepared and shown to be highly active antimalarial agents in both rodents and primates. Among structural modifications prepared, including Nlo-alkyl and C2-substituted analogs, removal of the CBoxygen, and introduction of an imino side chain a t Cg, the imines of the Nlo-H acridinediones were the most active compounds obtained. The [3-(NJV-dimethylamino)propyl]imino derivative of 7-chloro-3(2,4-dichlorophenyl)-3,4-dihydro-1,9(W,l0~-acridinedione (9aa) proved to be highly active in advanced studies in primates.
To the chemotherapist the revelation of a new chemical class with potent activity against an important disease entity, which might portend a unique mechanism of action as well, is always exciting. Thus our interest was piqued some years ago by the report3 of the activity of acridine&one structure 1 against chloroquine-resistant strains of plasmodia. Later reports6' made it apparent that the structure of primary interest was 2. Although our early efforta were directed toward the delineation of the structural features required for activity within this system, we turned rapidly to improving the apparent shortcomings of 2, Le., limited solubility and a hint of toxic liability. Our initial success was reported in a patent.* We continued to refine and extend our work,B,1° and during this time further work from the Hoechst group also appears.11-13 (1) This is Paper 64 of a series of antimalarial drugs. For Paper
(2)
(3) (4) (5) (6)
(7)
63, see: Werbel, L. M.; Degnan, M. J. SyntheSi8 and Antimalarial and Antitumor Effects of 2-Amino-4-(hydrazinoand hydroxyamino)-6-[(aryl)thio]Quinazolines. J. Med. Chem. 1987,30,2151-2154. This investigation was supported by US.Army Medical Research and Development Command Contract DAMD 17-79C-9115. This is contribution 1888 to the Army Research Program in Malaria. Belgian Patent 818,048, Hoechst, Feb 13, 1975. Raether, W.; Fink, E. Tropenmed. Parasitol. 1977, 28, 268. Schmidt, L. H. Antimalarial Properties of Floxacrine, a Dihydroacridinedione Derivative. Antimicrob. Agents Chemother. 1979,16,475-485. Raether, W.; Fink, E. Antimalarial Activity of Floxacrine I. Ann. Trop. Med. Parasitol. 1979, 73, 506-526. Joyner, L. P. Chemotherapy of Protozoal Infections of Vekrinary Medicine. J. Protozool. 1980,27, 31A.
0
0
1
0
0
2
The exciting activity of our compounds and the time needed for the Walter Reed Army Institute of Research (8) U.S.4,291,034, Sept 22,1981; 7-Chloro-3-substitutedAryl-3,4
dihydro-l,9(2H,lOH) and 10 Hydroxy Acridinedioneimines Having Antimalarial Activity. Chem. Abstr. 1982,W, 66114. (9) Werbel, L. M.; Hung, J.; McNamara, D.; Ortwine, D. F. 3Aryl-7-chloro-3,4-dihydro-1,9(2HllOH)acridinedione, 1Hydrazones as Potent Antimalarial Agents. Eur. J. Med. Chem. 1986,20,363-370. (10) Hung, J.; McNamara, D. J.; Werbel, L. M. Synthesis of 3,4Dihydrothioxanthene-lI9-dione Analogs ae Potential Antimalarial Agents. J. Heterocycl. Chem. 1983,20,1575-1580. (11) Durckheimer, W.; Raether, W.; Seliger, H.; Seidenath, H. 10Hydroxy-3,4-dihydroacridine-l,9(2H,1OH)-diones.A New Group of Malaricidal and Coccidioetatic Compounds. Arzneim.-Forsch./Drug Res. 1980,30(11),1041-1046. (12) Raether, W.; Fink, E. Antimalarial Activity of Floxacrine (HOE 991). 11. Studies on C a d Prophylactic and Blood Schizonticidal Action of Floxacrine and Related Dihydroacridinedioneo Against Plasmodium yoelli and P. berghei. Ann. Trop. Med. Hyg. 1982, 76,507-516. (13) Winkelmann, E.; h t h e r , W. Antimalarial and Anticoccidial Activity of 3-Aryl-7-chloro-3,4dihydroacridinal,9-(2H,lOH)diones, 1-Imines, 1-Aminea, 1-Oximes, 1-Hydrazoneaand Related Compounds. Arzneim.-Forsch./Drug Res. 1987, 37, 647-661.
0022-2623/92/1835-3429$03.00/00 1992 American Chemical Society
3430 Journal of Medicinal Chemistry, 1992, Vol. 35, No. 19
Kesten et al.
Scheme I
0 I
I
1) NaOH 2)
0
0
0 bAr I OH
4
CHO
5
U
Ar R
Table I. Preparation of Cyclohexan-l,3-diones
0
yield, purified % 1st 2nd 3rd purification analysis no. R mp, OC (lit. mp, OC) step step step proc solvent(a)" formula (h0.40) 4a 3,4-C1&& 198-200 (190-192)q 70 40 A R-2-propanol ClzHloClzOz C,H,Cl 4b 3-CF,-C6H, 173-176 73 43 A T-toluene C13HllF30 C,H,F 40 CBHll 162-163 (154-156)' 76 35 A R-acetone, ether CIZH18OP C,bH 4d 4-CF3-C& 164-167 32 43 A T-toluene C13H1102F3 C,KF 4e 1-CloH7 157 92 71 A T-toluene Cl6H1402&.7HzO C,H,H20 4f 3,4,5-(OCH,)&H2 155-159 100 69 A T-ether C16H1806.1.OH20 C,H,H20 4g 4-Me2N-c6H4' 207-210 100 63 A none C14HlBN02Na C,H,N C,H,Br 4h 3-Br-CBH4 181-183 97 A T-toluene C12HllBr02 4i 2,6-Clz-C6H3 205-207 94 A T-C& C12H10C120 C,dH,Cl 4j CBHS 192-194 (187-189)' 72 45 A T-toluene C1zH1102.0.1H20 C,H A T-ether CllHl6O2 4k (CH& 166-168 (170.5)O 14 39 41 2-Cl-CBH4 150-152 (153-154)' 64 26 A R-CH2C12, CHSCOzCzH, Cl2HllClOZ C,fH,CI 4m 4-CBH11-C6H4g 238-240 85 57 A T-CH30H, ether Cl8H2202 C,hH 4n ~ - C F ~ - C B H ~ 194-197 86 49 A T-toluene C13HllF302 40 4-CH3-CBH4 180-182 (165-167)' 93 77 A T-toluene C13H1402 4p 2-OCH3-CeH4 145-148 (145)' 98 73 A T-toluene C13H1403 4q 4-OCH3-CeH4 178-181 (177-178.5)' 97 40 A T-toluene C13H1403 4r 2,4-C12-C& 192-196 (174-181)' 78 67 A R-DMF, CH3C02C2H6 C12H10C1202 48 4-C6HdN 197-198 79 71' A2 R-DMF CllHllNO2 C,H,N 182-184 67 40 4t 2,4-Cl&H3(4-CH.J A3 R-CH3CN C13H12C1202 73 ltv 4U 3,4-C&-C6H3(4-CHJ 110-136 A3 R-pet. ether C13H12C1202 4V 4-SCH&H4 A 4W 4-NO2-C6Ht 225 dec 40 A4 R-CH3CN C12HllN04 C,H,N 4 s 4-CF&BH4(4-CzHS)' 160-163 90 81 70 A5 R-CHC13 C16H16F302 C,'H 4y 4-CF3-C6H4(4-CHJ0 178-180 90 61 79 A5 R-CHCl3 C14H13F302 42 2-CSH4N 160-161 78m 33 A2 R-CH2C12, CH~COZC~HS CiiHiiNOz C,"H,N 70 5V A6 T-aq.AcOH 4aa 3,4-C12-C&(4-C&,) 85-90 C18H14C1202 9 A2 R-CHSCN 4bb 3-CF3,4-Cl-CBH3P 192-194 C13H10C102F3 "R = recrystallized, T = triturated. *Anal. calcd for C, 74.19; found, 73.57. 'Isolated as sodium salt. dAnal. calcd for C, 56.06; found, 55.64. OLit. mp = 170.5 OC. (Wallach, 0. Annalen 1912,394,376. Norris, W.; Thorpe, J. F. J. Chem. SOC.1921,119, 1199.) 'Anal. calcd for C, 64.73; found, 64.00. #Benzaldehyde prepared as described "Anal. calcd for C 79.96; found, 79.33. 'Yield from the cyclohexene-carboxylic acid. Crude yield. 4-Position of NOz group assigned from the para splitting pattern in the NMR. 'Anal. calcd for C, 63.37; found, 62.87. "Yield of the cyclohexene carboxylic acid, sodium salt. "Anal. calcd for C, 69.82; found, 69.37. OCie, trans mixture. PBenzaldehyde prepared as described previously.B PSchoen, K.; Pachter, I. J., US Patent 3503990,1970. 'Tamura, Y.; Yoehimoto, Y.; Kunimoto, K.; Tada, S.; Tomita, T.; Wada, T.; Seto, E.; Murayama, M.; Shibata, Y.; Nomura, A.; Ohata, K. J. Med. Chem. 1977,20,709. Hinkel, L. E.; Ayling, E. E.; Dippy, J. F. J. J. Chem. SOC.1935, 539. *Yieldsare in enamine steps from cyclohexanedione.
7-Chloro-3-substituted-3,4-dihydro-1,9(2H,lO~-acridinedionesJournal of Medicinal Chemistry, 1992, Vol. 35, No.19 3431 Scheme I1
+&ao NaH
0
R1
to complete the needed extensive biological studiea in their effort to work toward selection of one of these analogs for INDf i i i has necessitated some delay in the publication of this information. However in this manuscript we are now able to report full chemical and biological details of the development of a series of structures 3 with potent antimalarial properties devoid of the negative manifestations of the acridinediones 2.
&JR3
DMF
I
RZ
Ri
B
Scheme I11 0
H
CF3
Scheme IV
+ O-3CF 0 CF3
-
NH2 0
CH3HN
0
znCI2
c F3
12
CF3
Scheme V
CF3
1
CF3
Table 11. 3,4-Dih~~l,S(W,lOH)-acridinediones
RO
0
W IP W
0
vield.
tu
Durification
8.
8b &
8d 8e 8f
as
8h 8i
ai
8k 81 8m 8n 80 8P 81 8s 8t 8U 8V 8W 8X
8Y 82 8u
8bb &C
Ma 8ee 8ff
c1 c1 CI CI H c1 CI c1 c1 CI CI CI CI c1 c1 H CI CI CI CI c1 c1 CI CI CI CI CI CI CI CI
I
8ii
CI CI CI
Sii
O d
%g
8hh 8U 811 8mm ann Boo SOP
s9q 811 8ss 8tt
8uu 8W 88 u 8m 822
CI CI CI Cl CI CZHS CI CI Br H Br H CI c1 c1
CI H
H H H H H H H H H H H H
H H H
H H H CI H H
H H H H H H H H H H H H H H H H H H H H
H H
OH OH H OH OH OH ONa OH OH OH CH3 OH OH H CH3 H OH H OH (2-CH3) OH (6-F) OH CZHS n-C4HB CH&&IH, OH H CH2CH==€Hz n-c&I13
H H OH OH OH OH OH H H OH H (5Br) H H H H H H
202-283 dec 255-258 dec >325 265-267 264
236-238 277-279 244-248 234-236 242-245 dec 226-22a 250 dec 260-261 >280 276 dec 342-346 254-255 >350 236 dec 239-242 dec 244 dec 262-266 271-275 270-274 243-245 315-316 273-275 215-218 353-355 310-312 327-330 269-271 267-268 230 dec 255 dec
>360 >360 229-240 263-265 347-348 326-329 330
>300 >300
18 68
34
B B D
55 47 29 25 53 57
B B B
70
B F B B G
36 72 74 58 31
66 65 38 30 46 37 43 26 28 44
50 42 30 51 54 59 38 65 47 83 50 50 78 50 13 45 58 54 74 89
Bd
B‘ B
F D
B D B B
B F F F
B F
F F F F B
B B B B F Ff
B F
I F F
D D D
T-cH~OH. DMF R-DMF T-aq. CzHsOH T-CzHsOH T-CHSOH
T-C&OH R-CH,OH, ether T-CzHsOH T-GHSOH T-CzHim R-CH&N T-CZHSOH R-CH&lzCzH5OH T-CH30H R-DMFC&ISOH T-C&OH T-CzH,OH T-CH,OH-aq NaOH (tr) T-DMF TCZH5OH T-C&150H R-CHzClzCH3COzEt R-CHzCIzCH3C02Et R-CHzCIzCH&OzEt T-DMFCH30H T-DMFCH,OH R-CHZC12CH&OzEt R-CH&OzCzH, T-DMFCH,OH-ether R-DMFXH3OH T-DMFCH30H R-DMF T-CzHsOH R-CHSOH T-CzHsOH T-DMFCH,OH*ther T-DMFCH,OH*ther T-CzHsOH R-DMFCH,OH R-DMFCH,OH R-DMFCH,OH T-DMFCH30H-ether T-aq. NH40H (dilute) T-aq. NH40H (dilute) T-aa. NH.OH (dilute)
C16Hl~OZ c&i&rF3Noz C&14F3NOz C&I,CIF3NOz CanH,nClN09
c-JH;acwo;
5 rn cc
I %
a
a
?.
7-Chloro-3-substituted-3,4-dihydro-l,9(2H,l OH)-acridinedicmes
Journal of Medicinal Chemistry, 1992, Vol. 35, No. 19 3433
Chemistry The general synthetic3 approach utilized in preparing precursors is the 7-chloro-ldhydroxy-3-aryhcridinedione outlined in Scheme I. The requisite benzaldehyde was allowed to react with acetone in the presence of base (procedure A) or with l-(triphenylphosphorany1idene)-2propanone in toluene (procedure A2) to provide the corresponding l-aryl-l-buten-3-one. The arylaldehyde could also be allowed to react with 2-butanone under acidic conditions to provide exclusively the 4-aryl-3-methyl-3buten-2-one (procedure A3). The unsaturated ketones were treated with the sodium salt of diethyl malonate and the intermediate 6-aryl-2-hydroxy-4-oxo-2-cyclohexene-lcarboxylic ester was hydrolyzed and decarboxylated to give 5-aryl-1,3-cyclohexanediones(4)(Table I). Several 5-alkyl-1,3-cyclohexanedioneswere also prepared similarly. Additional substitution of the 1,3-cyclohexanedioneacould be achieved by reaction of their pyrrolidinyl enamines with LDA and methyl or ethyl iodide followed by acid hydrolysis (procedure A5).'"" The 5-substituted 1,3cyclohexanedioneswere treated with o-nitrobenzaldehyde to furnish 7-chloro-3-aryl-3,4-dihydro-lO-hydroxy-1,9(W,lOH)-acridinediones (5). An unusual, somewhat limiting, but well-documented, feature of the latter reaction is the simultaneous introduction of a chlorine atom into the 7-position. The importance of this halogen for biological activity is addressed later. An early effort was made at acylation of the N-OH function of the acridinediones with the thought that this might aid in solubilization of the system as well as providing extended duration of action. Despite the report in the original patent? several attempts provided instead C1or C4-substitutedproducts such as 6 or 7 (see Experimental Section).
xBxxx
xxxxx
GXhBB
BBs8b
We then sought to increase solubility by derivatizing the ketone at the l-position with a nitrogen containing functionality, 9. We learned early on that this approach not only improved the physical properties of the series but led to improved biological activity and eliminated the requirement for the Nlo-hydroxy function. Therefore an extensive exploration was undertaken. The 7-chloro-3-aryl-3,4-dihydro-l,9(2H,10H)acridinediones (8, R1= H) (the deshydroxy analogs) could be prepared by treating the parent Nlo-hydroxy compounds with PC13 However this procedure limited analog synthesis to those with a chlorine at C,. This shortcoming was circumvented by development of a much more flexible route involving (Scheme 11)the reaction of an appropriately substituted isatoic anhydride with a 5-aryl-1,3cyclohexanedione. The conversion of anilines to isatoic (14) Szmuszkovicz, J. Enamines. In Adv. Org.Chem. Methods and Results. Raphael, R. A., Taylor, E. C., Wynberg, H., Eds.; Interscience: New York, 1963; Vol. 4, p 98. (15) Bryeon, T. A.; Gammill, R. B. Enamine Chemistry I. Carbanion Alkylations. Tetrahedron Lett. 1974, 3963-3966. (16) After Telschow, J. E.; Reusch, W. A Study of the Enamino Ketone Variant of the Robinson Annelation. J. Org. Chem. 1975,40,862-865. (17) Stork, G.; et al. The Enamine Alkylation and Acylation of Carbonyl Compounds. J.Am. Chem. SOC.1963,85,207-222.
w P w
Table 111. Imines of 7 - C h l o r o - 3 , 4 - d i h y d r o - l O - h y d r o x y - l , 9 ( 2 H . 1 e s O
N
P
/R1
3 F
E \ 0
no. 3a 3b 3c 3d 3e 3f
s 3h
3i 3j 3k 31 3m 3n 30 3P 39 3r 3s 3t 3u 3v 3w 3s 3Y 32 3M 3bb 3cc 3dd 3ee 3ff
3M
3hh 3ii 3jj 3kk 311 3mm 3nn 300 3PP 39Q 3rr 3ss 3tt 3uu 3vv 3ww 3xx
R1
mp. "C 209210 185-187 13e135 212-213 178-180 182-184 205-206 171-174 134-136 111-113 135-137 84-88 155 195-197 15&154 184-185 190-192 100-105 158161 231 dec 163-179 122-126 P.S. 175-179 196197 112-115 187-188 144-149 248 dec 198-200 100-105 185-187 167-168 169.5-170.5 10&113 142-144 87-90 200-202 144-148 197-199 12(t124 168-171 165-166 191-192 167-170 dec 133-140 182-183 182-183 155-157 122-125 87-90
yield, purified % 73 52 79 61 87
74 72 91 91
90 83 54 95 87 98 61 15 65 83
purifkation solvent(s)'
proc. Hb Hb
formula
H H H H H H H H H H H H H' H H
C,H;N,CI,H,O C,H,N,CI,F C,H,N.CW C,H,N,Cl,F,HzO C,H,N,Cl C,H,N,CI CJW C.H,N,CI,CI-,HzO C,H,N,CI,HzO C.H.N
C;H;N,CI,H~O C,H,N&,Cl,HzO C,H.N
80 48
Hb
98 96 62 68 83 97 90 73 32 88 100
H H H H H H H' H HI H
88
74 36 79 90 88 70 95 81 83 52 38 15 90 80
88 40 77
d w i n (*0.40)
H H H H H H
H H H H H H H' Hh H H H H
H
none T-CH&N R-CzH,OH T-n-C7H,, T-CzH50H R-ether R-CHCl3 T-c6H1Z
T-n-C,H,, T-n-C,H,, R-CHFN R-CH&OzCzH, R-CHFN T-CH,&OzCzH, T-n-C,H,, R-CH3COZCzH5 T-n-C7H,, R-C& T-n-C,H,, R-toluene T-CH3COzCzHS R-toluene, CsHI2 R-CH&lz:tol.:CBH14 R-CHZClz:tol.:C6H,, R-CHzCIz:to1.:C,H,, R-CHzC1z:C6H,z R-CH2Clz*ther
H H H H H H H H H H H H H H H H H H H H H H H H H
C,H,N,CI,Cl-.F.H,O C.H.NC1.F
k
7-Chloro-3-substituted-3,4-dihydro-1,9(2H,lOH)-acridinedionesJournal of Medicinal Chemistry,1992, Vol. 35,No.19 3435
anhydrides was utilized to provide a variety of substituents in the C,-C, positions. N-unsubstituted isatoic anhydrides could readily be alkylated, and these N-alkyl intermediatea allowed the preparation of several Nlo-alkylacridhediones. These Nlo-alkylacridinediones had very limited antimalarial activity, and attempts to prepare the imines led only to aromatized products so this area was dropped. The possibility existed that the product of the reaction between the 4-substituted-5-aryl-1,3-cyclohexanediones and o-nitrobenzaldehydeas well as with katoic anhydride could be the 4-substitutad isomer 10 and not the predicted (on steric considerations) 2-substituted isomer 8. To addrege this poesibility, a long-range W-'H N M R correlation experiment with fixed evolution time (XCORFE)F9designed to exhibit coupling between 13C and 'H nuclei separated by two or three bonds, was performed. If the product was 8 (& = CH3),a threebond coupling between the protons of the 2-CH3group and the l-carbonyl carbon should be evident. Such was indeed the case. If, on the other hand, the product was the 4-methyl analog (i.e. 10, R3 = CH3),no coupling would have been observed due to the five-bond distance between the nuclei. The same coupling was observed for the product with isatoic anhydride confirming the structures as 2-substituted.
10 -
d
Most N-OH and N-H acridinediones COL e hdrivatized readily by treatment with simple a k y l ~ - s More . difficulty was encountered with isolation of imines from longer chain amines because of their reduced tendency to crystallize. The intermediate carbethoxycyclohexanedione (precursor of 4) could also be isolated and converted to the corresponding 2-carbethoxyacridinedionebut imino derivatives of these analogs could not be prepared, probably because of the enolic character of the ketone which was now part of a &keto ester system. Several C2-substituted acridinediones and the corresponding imines were prepared. These compounds can exist as cis,trans isomers. In two cases we were able to separate the mixtures by column chromatography (9kk, 911,and Qnn,900). Preliminary stereochemical assignmenta were made on the bask of the NMR spectra of these compounds. However since biological activity was not affected in these cis,trans pairs, further studies to define their stereochemistry were abandoned. It was important to examine some of the many features of this active structure in terms of the role they play in the biological activity. Exploration of a variety of these are described below. To observe the effect of removal of the C9-oxygen,a few representative compounds were synthesized (Scheme III). 2-Aminobenzaldehyde or 5-chloro-2-aminobenzaldehyde was allowed to react with a 5-substituted l,&cyclohexanedione in the presence of piperidine to afford the corresponding 3,4-dihydro-3-substitu~-l(~-acridhone. Treatment of this with NJV-dimethyl-l,&propanediamine and a catalytic amount of p-toluenesulfonic acid gave the imine derivative, whereas oxidation with m-chloroperoxybenzoic acid provided the NIo-oxide. Alternatively, introduction of an amino side chain at C9 was accomplished by two separate pathways. In the first (Scheme IV) 2-amino-5-chlorobenzonitrile was allowed to
Table IV. Imines of 3,4-Dihydro-1,9(2H.lOH)-ncridinedionea
0 Ip
0 Q1
R3
no. 9a 9b 9c 9d 9e 91
%
Oh 9i
oi
9k 91 9m 9n 90
9P 99 9r 9s 9t
9u 9v
9w
ox
4r 9z 9aa 9bb 9cc
9dd 9ea 9ff %6
9hh 9ii 9ii 9kk 911
a
R,
H H H H H H H H H H H H H H H H H H H H H H H H H H H
c1 CI CI CI
I c1 c1 c1 CI CI c1 CI NO2 c1 CZHS c1 Br (5-Br) Br H OCH3 CI (5x1) F c1 c1 c1 H (542) H(sa)
H H H H ~-
CF3 c1 H (5,aciz) c1 Cl H CI H H CI H (cis-2-CH3) CI H (tram-2-CH3) c1 H c1 (2-C.H.1‘ .~ H (cis-2-CH3) c1 H (tram-2-CH3) CI H (2-CzHsp CI z8H3 H CI H (6-Cl) H CI H H (2-CHz-C8H,)” c1 c1 H (2-CH3)” H c1 c1 H ~
9nn 900 9PP 9qq 9rr 9ss 9tt
9uu
ow
OWW
R,
v
~
mp, “C
yield, purified k proc.
164-165 205-207 295-298 dec 273-275 dec 227-229 275-276 233-235 14tF152 262-266 141-143 >300 154-157 245-246 172-174 206-208 217-218 186-187 224-225 197-200 228-232 163-165 221-223 184-185 213-215 168170 206207 24%250
75 58 82 8 8 91 69 77 78 53 29 82 69 79 69 82 89 69 52 71 81 81 62 6 39 9 60
201-204
204-205 185-187 208-210 203-205 202-205 168-170 147-150 229-231 198-200
94 53 67 8 4 81 6 0 73 21 5 8 4
169-170 171-172 117-120 228-230 200-201 223-225 >69 165-178 157-161 176177
20 22 44 63 69 9 0 71 36 8 0 74
0 6
8 6
H H H H H H H H H H H H H H H H H H H H H H H H H H H‘
none R-CZHSOH R-DMF R-DMF none none none
H Hd H H
R-CHzCl&H14 R-CHCI3CH3OH R-CH3COzCzHs R-CHzCIzCH&OzEt R-CZHSOH R-CZHSOH none R-CH&N R-CZHSOH R-CH3CN
H H H Hd Hd H
analysie
purification solvent(s)”
fomula
(*0.40)
R-CBHIZ
R-DMF R-CHFN none none R-CH&lz-CH3COzEt R-CzHsOH none none none none none none none none R-CZHSOH R-CH&O&HS R-CHzCI~CH&OzEt none R-CH3OHCH3COZEt
y
Hd Hd H H H H Hd H H Hf
1 R-etherpet. ether R-CzHsOH none none R-CHCl3CH3OH R-etherpet. ether none T-CH,OH-ether
H H H H H H H 9 H
R E 0
J
::
a
7-Chloro-3-substituted-3,4-dihydro-1,9(2H,l0H)-acridinediones Journal of Medicinal Chemistry,1992,Vol. 35,No.19 3437
react with a 6-substituted-l,3-cyclohexanedionein the presence of p-toluenesulfonic acid to afford S-chloro-2[(6-substituted-3-oxo-l-cyclohexenyl)amino]benzonitrile. Zinc chloride effected cyclization to 9-amino-7-chloro3,4-dihydro-3-substituted-l(2H)-acridinonewhich when allowed to react with iodomethane and sodium hydride furnished 7-chloro-3,4-dihydro-Q-(methylamino)-3-substituted-l(WI)-acridinone. The alternative pathway (Scheme V) involved treatment of 7,9-dichloro-3,4-dihy&& [4-(trifluoromethyl)phenyl]-1(2H)-acridinone with NJV-dimethyl-l,3-propanediamine to give 7-chloro-9[ [3-(dimethylamino)propyl]amino]-3,4-dihydro-3-[4-(trifluoromethyl)phenyl]-1(2H)-acridinone. The dichloro compound had been prepared by chlorination of 7chloro-3,4-dihydro-3- [4-(trifluoromethyl)phenyl]-l,Q(W,lOH)-acridinedione with phosphorus oxychloride. Unfortunately, all such major structural changes resulted in elimination of antimalarial activity. Suppressive Antimalarial Screening in Mice All of the compounds listed in Tables II-IV were tested initially against a normal drug-sensitive strain of Plasmodium berghei by the parenteral routeem The compounds were dissolved or suspended in sesame or peanut oil and were administered to mice in a single subcutaueous dose 72 h postinfection. The antimalarial activites are summaried in Tables V-VII.
5855
5cc
-5 xxxx
9 xxx
As a class, the 3-aryl-l0-hydroxy-3,4-dihy~oacridinel,Q(W,lOH)-dionesare very potent antimalarial agents, many of them showing curative activity below dosages of 20 mg/ kg. The best compounds in this group (Table V) were the 3-(4-trifluoromethylphenyl)(floxacrine),the 3(2,4-dichlorophenyl),the 3-(3,4-dichlorophenyl)-2-methyl, and the 3-(2,4-dichlorophenyl)-2-methylanalogs. Contrary to a previous report,2l we have found that removal of the Nlo-oxygendoes not completely eradicate antimalarial activity. The Nlo-Hacridinediones that we prepared generally displayed a high level of activity, albeit not quite that of their Nlo-OH analogs. The two best compounds in this group were the 3-(2,4-dichlorophenyl) and the 3-(4-trifluoromethylphenyl)derivatives. Except for the Nlo-allylderivative, which showed modest activity, the Nlo-alkylacridinediones reported here were all inactive. Imines of the Nlo-OH acridinediones showed activity roughly comparable to their precursors although some toxicity was evident at higher doses. Higher molecular weight sidechains tend to improve activity somewhat whereas those containing cyclic moieties show a small decrease. Imines of the Nl0-Hacridinediones were surprisiiy the most active compounds synthesized for this study, notably those of the 3-(2,4-dichlorophenyl) analog. Nearly all of the imines of 7-chloro-3-(2,4-dichlorophenyl)-3,4-di(18) Castle, R.;Adachi, K.; Guther, W. D. Cinnoline Chemistry XII. The Synthesis of 6-fluom-4methylcinnolineand other Cinne lines as Potential Antitumor Agents. J. Heterocycl. Chem. 1965,2,459-462. (19) . , Hardtmann. G. E.: Koletar, G.: Pfister, 0.R. The Chemistry of 2H-3,1-Benzoxkine-2,4(lH)dione (Isatoic Anhydridee) 1. The Synthesis of N-substituted 2H-3,1-benzoxazine-2,4(1H) diones. J. Heterocycl. Chem. 1975, 12, 585. (20) Osdene, T. S.; Russell, P. B.; Rane, L. 2,4,7-Triamho-6orthesubstituted Arylpteridines. A New Series of Antimalarial Agents. J. Med.Chem. 1967,10,431-434. (21) Raether, W.; Durckheimer, W. Abstract of the 4th Intl. Congress of Parasitology. Congress Organizing Committee: Warsaw, 1978; Section D, p 105.
3438 Journal of Medicinal Chemistry, 1992, Vol. 35, No. 19
Kesten et al.
Table V. Effects of 7-Chloro-3-substituted-3,4-dihydro-lO-substituted-1,9(2H,10H)-acridinediones against Trophozoite-Induced P. berghei in Mice R,
+y& 6\
5
yo
4
R3
b
no. 8a 8b 8c
8d 8e 8f 813
8h 8i 8j Sk 81 8m 8n 80 SP 8q
8r 8s 8t
8u 8v 8w 8x 8~ 82 8aa 8bb 8cc
8dd 8ee 8ff 8gg
8hh 8ii 8jj 8kk
811 8mm 8nn 800 ~ P P 8qq
8rr 8ss 8tt
8uu
8vv 8ww 8xx ~ Y Y 822
8aaa Bbbb 8ccc
8ddd 8eee 8fff 8ggg
R1
c1 c1 c1 c1 c1 H c1
c1 c1 c1 c1 c1 c1 c1 c1 c1 H c1
c1 c1 c1 c1 c1 c1
c1 c1 c1 c1 c1 c1 c1 I c1 c1
c1 O2N
c1
c1 c1 c1 c1 H5C2
c1
c1
Br
H Br H
c1 c1 c1 H3C0 c1 H F Cl c1 H
R2 H H H H
c1 H H H H H H H H H H H H H H H H H
R4 OH OH OH ONa H OH OH OH H OH OH OH ONa OH OH OH CH3 OH OH H CH3 H OH H
640 5c 5c 5c 5c 5.3 2C (12.6) 0.3 1C (12.7)
2c (11.2)
3 c (3.4) 4C (13.7) 7.0 5.3 5c 4 c (7.9) 2c (11.2) 0.5 3C (11.5) 0.0
4C (14.6) 0.2
5c 5c 0.2
AMST or C after single sc dose, mg/kg 320 160 80 40 5c 2C (11) 10.8 5.0 1.7 0.3 8.3 3.5 5c 3C (13.4) 12.1 8.8 7.8 10 3C (16.0) 13.8 3.3 2.3 0.3 3.1 1c (7.7) 5.1 0.1 2.9 2.5 6.5 1c (10.2) 1c (7.7) 2.1 5c 5c 5c 5c 2.3 2c (5.7) 6.9 1.8 2.7 1.3 1.5 1C (6.6) 5.8 1.6 3C (6.8) 2.5 1C (10.7) 1C (9.2) 5.9 1.5 3C (23.9) 1C (5.8) 5.1 0.2 -0.2 4.0 2c (9.3) 2c (5.7) 5.6 0.2 0.0 3.2 1.6 3C (15.6) 9.6 0.0 0.6 4 c (9.4) 2c (9.9) 5c 5c 5c 5c 5c 5c 0.0 0.6
H H H H H H H H H H
5c 5c 5T 5T 2C (9.8) 3C (7.0) 1T (0.0) C2H5 0.4 n-C4H9 CH&jH, 1T (0.3) 4c (9.0) OH 0.4 H CH2CH=CH2 4C (15.0) 0.1 n-C6H13 1C (9.6) H 1C (6.9) H 4.1 OH
H H H H H H
OH OH OH OH H H
H H H
H H
c1
OH OH OH
5c 5T 2C (7.0) 2T (0.0) -0.2 0.0
1c (4.5) 0.4 12.6 1C (0.4) 2.8 1.3
4.6
OH
5c
5c
H
0.0
0.2
H H H H H H H
5c 4C (12.8) 3C (10.6) 5c 5c 8.3 2C (11.7) 5c 2.3 4.4
H H
0.0
2C (5.6) 1C (4.4) 4C (10.8) 8.5 2C (8.7) 4C (0.7) 2.9 0.4 5c 8.9 4C (17.8) 5c 0.3 2T (1.3)
H H H (2-CH3) H (5-C1) H (541)
4.5 3.1 2.2
5c 5c
-0.1
4T (2.0)
2T (4.0)
1.4 0.4 0.2 4C (8.8)
4C (9.6) 5T 7.0 2T (0.0) -0.2 0.2 4.6 0.2 1C (8.5)
4C (8.9)
0.1
0.7 1.8 1.0 1C (8.9) 2c (1.9)
3C (7.6) 9.0 4.5
1.7
0.1
0.0
8.3 6.9 3T 5.7 0.2 1.6
5c 5c 5c 5c
5c 5T 7.8
20 3.2 0.1 6.0 6.4
5.5
2.8 1.8 1.2
2.7 4.1 0.9
1.5 0.7
2.7 0.6 2.2 0.6
0.6 0.8 0.8 0.6
0.0
0.2 4C (9.8) 3.0 8.2
0.1
2C (19.4) 5.0 0.6 3.8 5.0 3.6 4.6 2.7 0.7 3.9 8.3 -0.3 -0.2
8.7 7.1
4C (15.8) 5c 1T (5.3)
3C (18.1) 2C (10.3) 3C (10.8) 8.2 0.1 1T (1.3) 1T (0.3)
7-Chloro-3-substituted-3,4-dihydro-1,9(2H,lO~-acridinediones Journal of Medicinal Chemistry, 1992, Vol. 35, No. 19 3439 Table V (Continued) no.
R1
8hhh
CF3 C1 C1 C1 C1 c1 C1 C1 c1 C1 C1 Cl C1 H C1 C1 C1 H
8iii 81jj
8kkk 8111 8mmm 8nnn 8OOo 8ppp 8qqq
8rrr ~SSS
8ttt ~UUU ~VVV
~WWW
8xxx 8yyy
R2 H H H H H H H H H H H H H H H H H H
R3 4-CF&& 4-CO2H-C6H4 4-OCH3-C&4 4-CSH4N 4-CbHIN 4-SCH3-C6H4 4-NO2-C& 4-CF&H4 4-CF&& 2-CbHdN 3,4-C12-C6H3 4-C1,3-CF3-CsH3 2,4-C12-C& 2,4-Cl&H3 2,4-C12-C& 4-CF3-C6H4 H 4-CF&,qH,
R4 640 H -0.1 OH 4T (0.9) H -0.1 OH 2.0 H 2.2 H 12.4 2C (13.3) H H (2-CzH5) 1.6 H (2-CH3) 4C (8.8) H 4.4 H (2-C6H5) 1.4 H 2C (5.7) OH (2-CH3) 5C H (641) 1.3 H (2-CH3) 5C OH (2-CH3) 5C H (2-CBHb) 0.0 H (6-C1) 0.4
hydro- 1,9(W,lOH)-acridinedione were totally curative at 20 mg/kg. Two of these, the Nfl-(dimethylpropy1)imino and the Nfl-(diethylethy1)iminoanalogs, were curative at doses as low as 5 mg/kg. In general, for all of these compounds a C3-aryl substituent is necessary for high activity. At C3 alkyl substituents impart marginal activity or are completely inactive. Among C,-aryl groups activity is enhanced by electron-withdrawing groups (e.g. halogen(s), CF,) and diminished by electron-donatinggroups (e.g. OCH3, (OCHJ3, CH3). Methyl groups in the Cz-positionare well tolerated in terms of antimalarial activity. Ethyl and phenyl groups at Cz have deleterious effects, the latter greater than the former. For these compounds, the C,-chlorine is necessary for the highest degree of activity. Unsubstitution or multisubstitution in positions C,-C, give agents of lowered effectiveness. Our limited experience with acridinediones containing reduced functionalities at C1or C9 indicates the diketo or keto-imino groups are necessary for activity. Walter Reed Army Institute of Research submitted imine 9aa for advanced studies in monkeys. Floxacrine in these studies administered for 3 days against infections of the Uganda Palo Alto (chloroquinesensitive) strain at doses up to 16.0 mg/kg led to recrudescences consistently.
At 16.0 mg/kg only two of six animals were cleared of the parasitemia, i.e., cured. In contrast imine 9aa cleared primary parasitemias of this strain at doses as low as 1.0 mg/kg. Cures were obtained at 4.0 mg/kg. Moreover 9aa was similarly effective against a chloroquine-,quinine-, and pyrimethamine-resistant (Smith) strain with clearance of parasitemia at 1.0 mg/kg, three to four cures at 4.0 mg/kg and complete cures at 16.0 mg/kg. In addition the Nhydroxy analog 3kkk effected parasite clearance against the resistant Smith strain at doses of 4.0, 8.0, and 16.0 mg/kg, and four primary infections were cured at doses
AMST or C after single sc dose, mg/kg 320 160 80 40 0.1 0.1 1T (-0.1) -0.1 0.1 -0.1 0.2 0.0 0.8 0.2 8.6 4.4 4.6 0.8 1.2 0.6 5C 2C (12.8) 7.5 5.7 7.3 2.4 1.1 0.4 0.0 1C (5.0) 1C (1.5) 1.1 0.7 5c 5c 5c 5c 0.1 -0.1 2C (17.1) 2C (15.1) 2C (10.8) 1C (9.3) 5c 5c 2C (14.1) 7.8 0.0 0 0.2 0.2 -0.4
20
3.9 0.9 2C (10.7) 8.2 5.2
of 8.0 and 16.0 mg/kg. Against the Uganda Palo Alto strain it c l d parasitemias through 2.0 mg/kg,cured one of two animals at 2.0 mg/kg, two of three animals at 4.0 mg/kg, and all animals at 8.0 and 16 mg/kg. Thus the acridinedione imines possess potent antimalarial properties, with the exciting potential for overcoming drug resistance. Further studies are in progress at Walter Reed toward a trial of one of these agents in man. Experimental Section Melting points were taken on a Thomas-Hoover capillary melting point apparatus. SatisfactoryEt and NMR spectra were obtained for all compounds. The IR spectra were recorded on a Nicolet 205X FT/Et. Maes spectra were obtained on a Finnigan 4000 mass spectrometer with an INCOS 2300 data system using direct introduction, electron impact at 70 eV, and 150 OC. Routine proton magnetic resonance spectra were recorded on a Varian EM-390 or XL-200 spectrometer operating at 90 or 200 MHz, respectively. Chemical shifts are reported in 6 units in parta per million downfield from internal tetramethylsilane; coupling constants are in Hertz. The XCORFE spectra for 8y and 8eee were recorded on a Varian XL-300 spectrometer equipped with a Varian 5-mm broad-band switchable probe tuned for 13C (75 MHz) on the observe coil and 'H (300 MHz) on the decoupler coil. The sample concentrationin each case was 60 mg in 0.6 mL of TFA-d. The XCORFE spectra were obtained in absolute value mode by acquiring 256 blocks of 2048 complex data points over a 13Csweep width of 15552.1 Hz for 8eee and 15267.2 Hz for 8y and a 'H sweep width of 3631.1 Hz for 8eee and 2919.7 Hz for 8y. A Tied evolution time of 3.57 ma and a 35- or &ma refocusing delay after the final Bird pulse were utilized. Filters were applied to the t2 fids (RE = 0.004, AF = 0.016 for 8eee; SE = 3.18, AF = 0.04 for 8y) and the t , interferograms (RE = 0.004,AF = 0.018 for 8eee; SE = 3.18, AF = 0.053 for 8y). The COSY spectra for 11 and 12 were acquired on a Varian XL-300 spectrometer operating at 300 MHz in absolute value mode. The sample concentration was 15 mg in 0.6 mL of DMSO-do The COSY experiments were performed using 256 blocks of 1024 complex data points over the entire *H spectrum using a 4 5 O observe pulse to minimize diagonal elements. Filters were applied to t2 fi& (RE = 0.012, AF = 0.046for 12; RE = 0.014, AF = 0.057 for 11) and the tl interferograms (RE = 0.006, AF = 0.023 for 11; RE = 0.007, AF = 0.028 for 12). Procedure A. The aldehydes used in Scheme I were generally obtained from commercial sources. The two, whose preparation are shown below, were synthesized in our lab on the basis of literature procedures. 4-Cy~lohexylbenzaldehyde.~ A mixture of 25.3 g (0.15 mol) of cyclohexylbenzene, 21.0 g (0.15 mol) of hexamethylenetetramine, and 300 g of trifluoroacetic acid was heated under reflux for 17 h. Concentration of the reddish-brown solution in vacuo
3440 Journal of Medicinal Chemistry, 1992, Vol. 35, No. 19
Kesten et al.
Table VI. Effecta of Imines of 7-Chloro-3-substituted-3,4-dihydro-l0-hydroxy-1,9(W,l0~-acridinediones against Trophozoite-Induced P. berghei in Mice
OH
no. 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 31 3m 3n 30 3P 3q 3r 3s 3t 3u
NR N(CHz)3N(Me)z N(CHz)sCH3
3v 3w 3s 3Y 32 3aa 3bb 3cc 3dd
B 3,4-Clz-C& 3,4-Clz-C&3 I-CFq-CfiH,
AMST or C after single sc dose, mg/kg 320 160 80 40 5c 5c 5c 3C (17.2) 3C (12.7) 5c 5c 3 c (9.9) 8.3 6.1 3T,2C 2T,3C 5T,lC 4c 5c 5c 5c 5c 3C (12.7) 3C (8.8) 3.7 8.7 2.1 0.9 5c 5c 4C (12.7) 2C (11.7) 8.5 4 c (4.7) 1c (9.3) 7.1 5c 2.6 4.3 4.0 1.0 5c 5c 4C (12.4) 9.6 6.9 5c 5c 3C (5.0) 2.8 3C (13.8) 1C (5.1) 1.0 5c 2C (11.5) 8.4 5c 4.4 5c 5c 5c 11.3 6.5 5c 5c 4C (8.7) 9.2 5.9 5c 5c 1C (9.6) 1C (6.1) 5c 3 c (7.4) 6.8 5c 0.9 1.7 1c (3.7) 4.1 1C (7.2) 1c (9.4) 4.1 5c 1.2 5c 2c (10.2) 9.4 5.3 1.6 3 c (10.8) 10.7 6.4 3.3 5c 4 c (8.8) 2C (8.3) 7.2 3.2 640
5c 5c 5c 5c 5c NH N(CHz)zNHCHzCH=CHz
8.8 5c 1C (13.0) 5c 4C (11.6) 3 c (12.1)
4.2 5c 2C (9.7) 4C (10.6) 3C (9.6) 5c
1.2 4C (8.0) 1C (6.3) 1C (7.9) 1C (7.9) 7.2
8.2 7.6 3.8 3.4 5c 5c 5c 1C (9.4) 4C (42.6) 4C (22.6) 2C (10.3) 8.0
5.3 4.8
0.6 8.2
1C (5.3) 5.6 6.6 5.6 1.4 2C (5.9) 6.6
1.2
2.0
3.0 1.6
5T 5c 5c 2.8 5c 5c 5c
5c 5c 5c
311 3mm 3nn 300 3PP 3w 3rr 3ss
5T 5c 5T 5c 4C (25.6) 4C,lT 5T 1C (11.1)
4T (0.5) 5T 4C (13.6) 4C (14.6) 5T 5c 4C (8.6) 5C 3C (9.6) 5C 4C (9.6) 5T 2C,3T 8.4 2C (8.6)
3.7 3T (4.6) 2C (10.3) 1C (9.6) 4.0 4T (0.6) 9.2 1C (11.9) 4.0 6.0 6.2 8.0 6.6 6.4 4.0 6.8 3.8
3tt 3uu 3vv 3ww 3xx 3YY 322 3aaa 3bbb 3ccc
3C,2T 1C,4T 5T 4T 5c 1C,4T 3C,2T
4C,lT 3CJT 2C,3T 4c 5c 5c 5c
5c 5c 2C,3T 5c 1c (9.5) 3 c (12.0) 4C (12.5)
6.1
5c 4C,1T
4C,1T 5C 2C,3T 5c 5c 5c 5c 0.7 5c 5c 3C (14.7) 5 c
5T 1C (10.9) 6.8 7.0 1C (9.6) 0.2 1C (9.1) 9.4 1C (9.6) 8.6 10.6 7.4
6.3 3.6
3ee 3ff 3gg 3hh 3ii 3jj 3kk
5c 5c
5T 5c 3C (11.6) 0.4 4C (10.6) 3C (10.1) 5c
20 7.1 2.5 5c 1C (10.5)
2 c (10.8) 2c (10.8) 3C (16.8) 4C (10.5) 4C (14.8) 3 c (10.0) 3 c (11.2) 0.4 3 c (10.2) 1C (8.5) 4.3 5c
5.6 5.4 4.4
1C (10.5) 1c (11.0) 2 c (10.1) 2C (14.0) 2c (12.0) 8.5 3C (13.0) 5.3
7-Chloro-3-substituted-3,4-dihydro-1,9(2H,lO~-acridinedionesJournal of Medicinal Chemistry, 1992, Vol. 35, No. 19 3441 Table VI (Continued) no. 3ddd 3e%e 3fff 3ggg 3hhh 3iii 3111 3kkk 3111 3mmm
NR
B
640
AMST or C after single sc dose, mg/kg 320 160 80 40
20
3nnn 3000 3PPP 3wq 3rrr 388s 3ttt yielded 25 mL of an oil which was taken up in 1200 mL of icewater, and the resulting two-phase mixture was stirred for 45 min. Saturated aqueous potassium carbonate was added until the mixture was clearly alkaline and then it was extraded with ether. The extract was dried over magnesium sulfate and concentrated in vacuo to yield 29.0 g of an oil which consisted of 92% of a major component according to gas chromatography and showed strong aldehyde bands in the infrared spectrum at 2740 (C(0)-H) and at 1705 (C-0) cm-'. Yield = 95%. 44Bis(met hy It hio)met hy 11-1-chloro-2- (trifluoromethy1)benzene.B To a stirred "eof 4.70 g (0.19 mol) of magnesium granules in 200 mL of freshly distilled tetrahydrofuran was added dropwise 41.78 g (0.16 mol) of 5-bromo-2-chlorobenzotrifluoride. After complete dissolution of the magnesium a solution of 20.00 g (0.16 mol) of methyl [(methylthio)methyl]sulfoxide in 20 mL of tetrahydrofuran was added dropwise and etirring was continued for 5 h at room temperature. The reaction mixture was filtered, and the filtrate was poured into 500 mL of 1N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with chloroform (500mL x 2). The organic solutions were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a brown oil. The IR and NMR spectra were consistent with the desired product. It was used directly in the next step without further purification. 4-Chloro-3-(trifluoromethyl)ben~nldehyde.~ To a mixture of 45.00 g (0.16 mol) of crude 4-[bis(methylthio)methyl]-1chloro-2-(trifluoromethyl)benzene,40 g of silica gel, and 40 g of water was added, dropwise, a solution of 37.80 g (0.28 mol) of sulfurylchloride in 100 mL of chloroform. The mixture WBB stirred at 0 "C for 2 h, after which 10 g of anhydrous potaseium carbonate was added, and the stirring was continued for another 10 min. The resulting mixture was extracted with chloroform (500 mL X 3) and filtered. The filtrate was washed with water, dried over magnesium sulfate, and filtered, and the solvent was removed in vacuo to give a brown oil. Distillation under reduced pressure afforded 28.54 g (86%, 2 steps) of a colorless liquid, bp 54 "C (10 m). The IR and NMR spectra were consistent with the desired product. 4-(4-Methylpheny1)-3-buten-2-0ne.2~ A mixture of 17.0 g (0.14 mol) of 4-methylbenzaldehyde, 80 mL of acetone, and 12.5 g of 50% aqueous sodium hydroxide in 450 mL of water was (22) Smith, W. E. Formylation of Aromatic Compounds with Hexamethylenetetramineand Trifluoroacetic Acid. J. Org. Chem.
1972,37, 3972-3973. (23) Hojo, M.; Maeuda, R.; Saeki, T.; Fujimori, K.; Tautaumi, S. An Alternative Synthetic Method for Aldehydes, Reaction of Methyl Methylthiomethyl Sulfoxide with Grignard Reagents. Tetrahedron Lett. 1977, 3883-3886. (24) Johnston, R. L.; Jones, L. A. Preparation of m- and o-Subetituted Benzalacetones. J.Chem. Eng. Data 1971,16,112-116.
stirred at room temperature for 3 days. The mixture was extraded with chloroform, and the organic extra& were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 22.9 g (97%) of the title compound as a yellow oil. This material was shown by VPC to contain 96% of a major component and was used as is in the next step. S-(4-Methylphenyl)cyclohexane-l,3-dione(40).*~ To 3.2 g (0.14 mol) of sodium spheres dissolved in 90 mL of anhydrous ethanol was added 23.0 g (0.14 mol) of diethyl malonate followed by 23.0 g of 96% 4(4methylphenyl)-3-buten-2-one. The solution was heated under reflux for 6 h, allowed to cool to room temperature overnight, and filtered to provide a crude solid. The fdtrate was concentrated in vacuo to a gum which was suspended in water and washed with chloroform to remove unchanged starting material and other organic-soluble impurities. The aqueous layer was concentrated in vacuo to a crude solid. This solid waa combined with the crude solid obtained above, 100 mL of 2 N NaOH was added, and the resulting solution was heated under reflux for 2 h. To the cooled, basic reaction mixture was added 100 mL of 5 N sulfuric acid. The suspension which reaulted was heated under reflux for 4.5 h, allowed to cool to room temperature, and filtered to provide, after trituration with toluene and drying, 21.4 g (77.3%) of the product, mp 180-182 "C. Compounds in Table I prepared similarly are designated by procedure A. Procedure A2. 6 44-Pyridinyl)-2-hydroxy-4-oxo-2-cyclohexene-1-carboxylic Acid, Ethyl Ester, Monosodium Salt. A solution of 21.4 g (0.20 mol) of 4pyridmecarboxaldehyde and 66.9 g (0.21 mol) of l-(triphenylphoephoranylidene)-2-propanone in 500 mL of toluene was heated under reflux for 1h and was then concentrated in vacuo to dryness. The residual solid was dissolved in 200 mL of ethanol, and the resulting solution was added to a mixture of 32.0 g (0.20 mol) of diethyl malonate in a solution of 4.6 g (0.20 mol) of d u m in 400 mL of ethanol. The resulting purplered solution was heated under reflux for 2 h, and then was concentrated in vacuo to approximately 200 mL. The suspension was cooled to 0 "C, and the solid was collected. It was triturated in 100 mL of ethanol to remove pink coloring, collected,and dried in vacuo at 80 "C for 6 h to afford 44.8g (79%) (25) Hinkel, L. E.; Ayling, E. E.; Dippy, J. F. V. Substituted Phenyldihydroresorcinols. J. Chem. SOC.1936, 539-540. (26) Neilsen, A. T.; Houlihan, W.J. Org. Reactions 1968, 16, 81. (27) Method of Boreche, W.Addition of Phenylacetic acid Ethyl Ester to Unsaturated Compounds. Chem. Ber. 1909,42,4496. (28) Chemistry of Isatoic Anhydride, Commercial Bulletin, Maumee Chemicals. (29) XCORFE is a standard pulee sequence supplied by Varian whose details are set forth in: Reynolds, W. F.; Hughes, D. W.; Perpick-Dumont, M.; Enriquez, R. G. J. Magn. Reson. 1985, 63, 413.
Table VII. Effecta of Imines of 7-Substituted-3,4-dihydr~3-substituted-l,9(~,lO~-acridinediones against Trophozoite-Induced P. berghei in Mice
W
IP IP
N
-0.0
R2
R,
no.
NR,
B
640
C1 C1 c1
H H H
3,4-CI2-C6H, 4-CF31C6H4-
se 9f
CI C1 CI
%
I
H H H H
3-CF3-C6H4 3,4-c1,c&r3 3,4-CIz-C& 4-CF3-C6H4
9h Si
c1 c1 c1 CI C1 C1 Cl OZN C1 H5CZ CI
H H H H H H H H H H H
4-CF&H4 4-CFS-C& 4-CF3-CeH4 4-CF3-C& 4-CF,-C& 4-CF3-CGH4 2-c1-c&14 4-CF3-C& 4-CF&& 4-CF3-C&
Br (5-Br) Br H H3C0 CI(5-Cl) F C1 CI CI
H H H H H H H H H
4-CF3-C6H4 4-CF3-Cd4 4-CF3-C& 4-CF3-C& 4-CF&& 4-CF3-CeH4 2-OCH3-C& 4-CH3-C& 2,4-ClZ-C6H3
Sa
9b SC
9d
si 9k 91
9m 9n 90
9P 9q
9r
96 9t
9u 9v
9w
ox
9Y 92
ou 9bb
9kk
H H CF3 CI H CI CI CI CI c1
911
CI
SCC
9dd sea
9ff %rt 9hh 9ii Sij
H (541) H (acu H H H ~5,acia H H H H H (2-CH3) Cis H (2-CH3) trans
9mm 9nn
CI C1
900
c1
H (2-C6H5) H (2-CH3) Cis H (2-CH3) trans
0
m
AMST or C after single sc dose, mg/kg 160 80 40 5c 4C (11.8) 3C (9.8) 3C,lT 5c 5c 0.0 0.6
5c
5c
2C,3T 1T (0.4)
2c,2T
5c 1T (2.5)
5c 1.2 3 c (20.0)
x
1CJT (14.0) 5c 5c 3 c (0.1) 5c 2 c (3.3) 5c 5c 1C (4T) 4C (1.3) 4T (1.4) 3C (9.6)
20
320
3 c (2T) 5c 5c 3 c (2T) 4C (49.6) 5c
5c 5T 5c 2 c (7.3) 5c 5c 3C (23.1) 1c (10.1) 5c 5c 2C (11.3) 4C (11.6) 5c 1T (1.9) 2C (10.3)
1C (14.4) 3T (1.5) 4C (8.0)
6.6 4T 4C (8.0) 3.0
9.2 3C (10.4)
5T 2 c (9.3)
5c 3C (17.6) 4C (9.6) 6.0 4C (1T) 5c 6.3 1c (8.9) 4C (13.6) 7.2
x
4C (13.6) 5.6 5.4 2C (10.3) 0.6 7.0
3 c (10.8) 2C (18.6) 2.2 2C (8.6) 2.8
C6Hll
2,4-CI,C& 4-CF3-CBH4 4-CF3-CeH4 4-OCH3-C6H4 2,4-ClZ-C&I3 4-C5H4N 4-SCH&H4 4-N0&& 2-C5H4N 3,4-C1&6H3
0.4 2C (25.7) 5T
5c
5T ZC (6.4) 2C (9.8)
5c
5T
5c 5c 1c (11.2)
5c
x 2C (6.5) 5c 3C (13.6) at 10 5T
0.2 5c 5T 2 c (8.7)
4T (IC) 6.7 6.6
5c 1C (7.4) at 5 5T 4 c (24.9) 7.1 4.5
0.0
5c
0.2
1c (9.3)
6.0 IT (5.3)
6.1
5T 5.5
0.7
1.4 5c
4C (14.9) 1.7 0.8 5c
5c
1T (0.5)
0.0
4T
7.7 3.1 0.5 0.0
1.2 0.7
4.3 4C (1T) 1C (11.8)
2.5 3C (12.8) 11.6
1.3 1C (9.8) 8.6
1.3 1C (4.6) 3.0
0.1 3.4 1.0
4C (1T)
5c
5c
4C (10.7)
4 c (21.0)
7.8
5c
5c
4C (15.0)
1C (7.2)
5.3
1T (2.3)
5c 3.1
2 c (12.2) 4C (3.0)
1C (14.2) 5c
1.7 5c
3.1 4C (10.7)
1c (2.7)
4 c (3.7)
5c
5c
5c
l C (11.0)
3,4-Clz-c&
5c
2.8
0.4
h
2 ;;; 3
a
7-Chloro-3-substituted-3,4-dihydro-1,9(2H,lO~-acridinedionesJournal of Medicinal Chemistry, 1992, Vol. 35, No. 19 3443 of the title compound, mp 262-263 OC. This product was used without further purification in the next step. S-(rdPyridhyl)-l,3-cyclohesanedione (4s). A turbid solution of 28.3 g (0.1mol) of 6-(4-pyridinyl)-2-hydroxy-4-oxo-2-cyclohexene-1-carboxylicacid, ethyl ester, monosodium salt in 75 mL of 10% sodium hydroxide, and 175 mL of water was heated under reflux for 2 h and then was filtered through Celite. The clear filtrate was acidified slowly with 16 mL of concentrated sulfuric acid, causing some frothing. The resulting solution was heated on a steam bath for 4 h and then was cooled to 5 OC and neutralized to pH 7 by the dropwise addition of 10% sodium hydroxide. The solution was seeded and cooled to induce crystallization. The suspension was kept at 0 OC for 16 h, and then the solid was collected and washed with water to remove inorganic salts. Drying in vacuo at 60 OC over phosphorus pentoxide for 16 h provided 13.5 g (71%) of the title compound, mp 195-201 OC. An analytical sample, mp 197-198 OC, was obtained by recrystallization from NJV-dimethylformamide and drying in vacuo at 60 "C for 16 h. Anal. (CI1HIINO2)C, H, N. Compounds in Table I prepared similarly are designated by procedure A2.
Procedure A3. 4-(2,4-Dichlorophenyl)-3-methyl-3-buten2-0110.~ Hydrogen chloride gas was bubbled
a
8 rb
into a mixture of 35.00 g (0.20mol) of 2,4-dichlorobenzaldehydeand 28.80 g (0.40 mol) of 2-butanone for 2 h at 0 "C. The resulting mixture was kept cool overnight, poured into 300 mL of 2 N sodium hydroxide solution and extracted with diethyl ether (500 mL x 3). The ether solution was dried over magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give a dark brown solid. Recrystallization from n-hexane gave 30.50 g (67%) of a white solid, mp 72-73 OC. The IR and NMR spectra were consistent with the structure of the desired product. b ( 2 p - D i c h l o r o p h e n y l ) - r d m ~ ~ l - l ~ y c l o h ~ s a(n4t~ ).o n e To a solution of 1.93 g (0.084mol) of sodium spheres in 100 mL of ethanol was added 12.33 g (0.077mol) of diethyl malonate. To the solution was added a solution of 16.04 g (0.070 mol) of 4(2,4dichlorophenyl)-3-methyl-3-buten-2-one in 100 mL of ethanoL The solution was heated under reflux for 2 h, during which time a white solid precipitated. The reaction mixture was concentrated to dryneas in vacuo, treated with 150 mL of 2 N aqueous sodium hydroxide, and fitered. The fitrate was heated under reflux for 2 h, cooled, and acidified with 50% sulfuric acid to pH 2. The resulting mixture was heated under reflux for 2 h, and the gummy material solidified when the reaction mixture was cooled. The solid was collected and recrystallized from acetonitrile to give 7.50 g (40%, three steps) of a pale yellow solid, mp 182-184 OC. The IR and NMR spectra were consistent with the desired structure. Compounds in Table I prepared similarly are designated by procedure A3. Procedure A4. 5-(4-Nitrophenyl)-l,3-cyclohexanedione (4w). To a mixture of 1.00 g (0.00531 mol) of 5-phenyl-1,3cyclohexanedione in 5 mL of concentrated sulfuric acid, cooled in an ice bath, was added dropwise 0.37 mL (0.00584mol) of concentrated nitric acid. The reaction mixture was stirred at 0 OC for 1 h The resulting solution was poured into ice-water. The solid which precipitated was collected by fitration, washed with water, and recrystallized from acetonitrile to give 0.50 g (40%) of the product as an off-white solid, mp 225 OC dec. Anal. (CizHiiNOd C, H, N. The position of the nitro group was shown to be on the 4position of the phenyl group by the para splitting observed in the NMR spectrum. Note that the product exists not in the cyclohexanedione but in the eneone tautomer illustrated:
by&
0
NO2
=..% NO2
NMR (90MHz, Me&30-d6): 6 = 2.2-2.9 (m, 4),3.3-3.7 (m, l), 5.3 (8, l), 7.6 (d, J = 9 Hz, l),8.1 (d, J = 9 Hz).
(30) Unterhalt, B.Unsaturated Oximes, 18. (Dichloropheny1)alkenones and Their Oximes. Arch. Pharm. 1978,31I, 262-267.
3444 Journal of Medicinal Chemistry, 1992, Vol. 35, No. 19 Procedure A5. 3-(l-Pyrrolidinyl)-5-[4-(trifluoromethyl)phenyl]-2-cyclohexen-l-one.14~16 A solution of 76.87 g (0.3 mol) of 5-[4-(trifluoromethyl)phenyl]-1,3-cyclohexanedione, 42.67 g (0.60 mol) of pyrrolidine, and a trace of p-toluenesulfonic acid in 500 mL of benzene was heated under reflux, using a Dean-Stark trap, until 0.3 mol of water had been collected. The solution was concentrated in vacuo to dryness. The yellow solid was recrystallized from tetrahydrofuran-ethyl ether to give 83.50 g (90%) of the product as a yellow solid, mp 168-169 "C. 4-Ethyl-3-( l-pyrrolidinyl)-5-[4-(trifluoromethyl)phenyl]-2-cyclohexen-l-one and 6-Ethyl-3-(1pyrrolidinyl)-5-[4-(triPluoromethyl)phenyl]-2-~yclohexen1-one. To a chilled solution (-65 "C) of 7.7 mL (0.055 mol) of diisopropylamine in 20 mL of dry tetrahydrofuran under nitrogen was added dropwise 23.1 mL (0.055 mol) of 15.25% solution of n-butyllithium in hexane. The mixture was stirred a t room temperature for 30 min. To the resulting solution of lithium diisopropylamidewas 4 d e d dropwise a solution of 15.45 g (0.050 mol) of 3-(1-pyrrolidinyl)d-[4-(trifluoromethy1)phenylJ -2-cy clohexen-1-one in 150 mL of dry tetrahydrofuran at -65 OC. The solution was stirred at room temperature for 1h, following which 4.8 mL (0.060 mol) of ethyl iodide was added at -65 "C. The resulting solution was stirred at that temperature for 1h, allowed to stir a t room temperature for 16 h and then poured into a saturated aqueous solution of sodium chloride. The organic layer was separated, and the aqueous layer was extracted with chloroform (200 mL x 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oily residue. It was chromatographed over 500 g of silica gel with CHC13-acetone = 4 1 as the eluent to provide 10.5 g (74%) of the major product (R = 0.5) as an off-white solid, mp 134-135 "C, and 1.0 g (7%) oda minor product as a white hygroscopic solid (R,= 0.4). The major product was a mixture of the cis and trans isomers of 4-ethyl-3-(pyrrolidinyl)-5-[4-(trifluoromethyl)phenyl]-2-cyclohexen-l-one and the minor product a mixture of the cis and trans isomers of 6-ethyl-3-(pyrrolidinyl)-5-[4-(trifluoromethyl)phenyl]-2-cyclohexen-l-oneaccording to their NMR spectra, gas chromatography analysis, and the precedent of the published literature.15s16Anal. Major product (C19H22F3NO) C, H, N, F. cis- and trans-4-Ethyl-5-[4-(trifluoromethyl)phenyl]1,3-~yclohexanedione (4x)." A solution of 6.8 g (0.020 mol) of the mixture of cis- and trans-4-ethyl-3-(l-pyrrolidinyl)-5-[4(trifluoromethyl)phenyl]-2-cyclohexen-l-one in 25 mL of ethanol containing 10 mL of 10% aqueous hydrochloric acid was heated under reflux overnight. The resulting solution was concentrated to dryness in vacuo and partitioned between chloroform and 2 N aqueous sodium hydroxide solution. The chloroform layer was evaporated to dryness to give mainly unhydrolyzed starting material. The aqueous sodium hydroxide solutionwas neutralized with 6 N hydrochloric acid and extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated in vacuo to give 2.9 g of the product. The unchanged starting material which was recovered above from the chloroform , extract was treated similarly to give an additional 1.1 g of the product. The total yield was 4.0 g (70%), mp 160-163 "C. The NMR spectrum and gas chromatography analysis indicated that the product was a mixture of cis and trans isomers of 4-ethyl5-[4-(trifluoromethyl)phenyl]-1,3-cyclohexanedione.Anal. (Cdi$'302), C, He Compounds in Table I prepared similarly are designated procedure A5. Procedure A6. 5-(3,4-Dichloropheny1)-4-phenyl-1,3cyclohexanedione (4aa). To a solution of 4.8 g (0.21 mol) of sodium spheres in 90 mL of ethanol was added 34.0 g (0.207 mol) of ethyl phenylacetate, followed by 37.0 g (0.160 mol) of 4434dichlorophenyl)-3-buten-2-one.The dark brown solution was heated under reflux for 3 h, then diluted with 500 mL of water. A gum wm precipitated from which the supernatant ww decanted. The ethanol-water supernatant was heated on a steam bath to remove the ethanol. The resulting aqueous solution was acidified with acetic acid and the light yellow solid which formed was collected. Attempted recrystallization from ethanol-water gave an oil. The mixture was concentrated in vacuo to remove the ethanol and resulted in a milky white solid suspended in the water and a gum which solidified on the bottom of the flask. The
Kesten et al. aqueous suspension was decanted, diluted with water and 30 I& of acetic acid, and filtered to give 19.28 g of the product, mp 85-90 "C.
Procedure B. 7-Chlor0-3,4-dihydro-lO-hydroxy-3-(4methoxyphenyl)-l,9(2H,10H)acridinedione (800).A mixture of 4.5 g (0.030 mol) of 2-nitrobenzaldehyde and 5.0 g (0.023 mol) in 35 mL of conof 5-(4-methoxyphenyl)cyclohexane-l,3-dione centrated hydrochloric acid and 35 mL of glacial acetic acid was heated at 85 "C for 4 h. The acidic solution was poured into 1.5 L of ice-cold water to precipitate a beige solid. Trituration overnight with ethanol at room temperature gave 7.0 g (82.7%) of the title compound, mp 255 OC dec. Anal. (CmHl6C1NOI)C, H, N. 8y: XCORFE NMR (300 MHz, TFA-d) 6 1.30 (d, J = 6.6 Hz, 31, 3.2-3.4 (m, 21, 3.6-3.8 (m, l),4.0-4.3 (m, l), 7.29 (d, J = 8.4 Hz, 1),7.53 (s, l), 7.60 (d, J = 8.4 Hz, 1),8.26 (d, J = 9.2 Hz, I), 8.49 (d, J = 9.2 Hz, I), 8.71 (s, 1). Compounds in Table I1 prepared similarly are designated procedure B. ProcedureC. 7-Chloro-3,4-dihydro-l0-hydroxy-3-[3-(trifluoromethyl)phenyl]-1,9(2H,lOH)-acridinedione,Sodium Salt, Monohydrate (Sa). To 1.0 g (0.00245 mol) of 7-chloro3,4-dihydro-lO-hydroxy-3-[ 3-(trifluoromethyl)phenyl]-1,9(W,lOH)-acridinedione suspended in 25 mL of methanol was added 0.14 g (0.00245 mol) of sodium methoxide. Most of the suspended material dissolved initially, and a new precipitate formed immediately after the addition. The yellow suspension was stirred at room temperature for 3 h, and the yellow precipitate was collected. Recrystallization from ethanol gave 0.8 g (73%) of the title compound, mp 315-320 "C dec, with darkening from 290 "C. Anal. (C20H,2C1F3N03Na-H20) C, H, N, C1, Na; H20: calcd 4.02, found 3.31. The NMR spectrum confirmed the presence of at least 1mol of water. Procedure D. 7-Chloro-3,4-dihydro-3-[4-(trifluoromethyl)phenyl]-1,9(2H,lOH)-acridinedione (8v). To a suspension of 7-chloro-3,4-dihydro-l0-hydroxy-3-[4-(trifluoromethyl)phenyl-l,9(2H,lOH)-acridinedione(10 g, 0.0245 mol) in 200 mL of chloroform at 5 "C was added dropwise 20.2 g (0.147 mol) of phosphorus trichloride. During the addition, an orangered solution was formed. It was heated to reflux for 1 h and then concentrated in vacuo to a dark tan solid residue, which was supended in 100 mL of ethanol. The solid was collected and dried in vacuo at 90 "C for 112 h to afford 6.3 g (66%) of the title compound, mp 342-346 "C. Anal. (C20H13C1F3N02), C, H, N, C1, F. Compounds in Table I1 prepared similarly are designated procedure D. Procedure E? To provide an example of a 10-hydroxyacridinedione without a chlorine a t C7 the literature procedure below was used. Only material containing a small amount of the C,-C1 analog could be obtained. Alternatively a 10-H example (8vv) was prepared cleanly by procedure F. 3-( 3,4-Dichlorophenyl)-3,4-dihydro-10-hydroxy-1,9(2H,lOH)-acridinedione(8f). A suspension of 2.35 g (0.0156 mol) of o-nitrobenzaldehyde, 4.0 g (0.0156 mol) of 5-(3,4-dichlorophenyl)-l,3-cyclohexanedione,and 3.4 g (0.031 mol) of hydroquinone in 30 mL of glacial acetic acid was heated at 80-90 O C . The resulting solution was treated with hydrogen chloride gas for 3 h while the temperature was maintained at 80-90 "C. The mixture was cooled and the resulting semisolid mass was triturated with water. The solid was collected, air dried, and triturated with ethanol to yield 4.0 g (67.9%) of the title compound as a very pale green solid, mp 257-260 "C dec, containing about 10% of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydr~lO-hydroxy1,9(2H,lOH)-acridinedione.Anal. Calcd for Cl9Hl3C12N03: C, 60.98; H, 3.50; N, 3.74; C1, 18.95. Anal. Calcd for ClsHl3Cl2NO3 + O.lC1): C, 60.41; H, 3.47; N, 3.71; C1, 19.71. Found: C, 60.22; H, 3.77; N, 3.66; C1, 19.45; C1-, 0.00. Procedure F. The NH isatoic anhydrides utilized for Procedure F, when not commercially available, were prepared by one of two routes-chromium trioxide oxidation of the corresponding isatinlaor condensation of the corresponding anthranilic acid with phosgene.28 The N-substituted isatoic anhydrides were synthesized by reaction of the NH isatoic anhydrides with the requisite alkylbromides and sodium hydride.18
7-Chloro-3-substituted-3,4-dihydro1,9(2H,1OH)-acridinediones Journal of Medicinal Chemistry, 1992, Vol. 35,No. 19 3445
6-Chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,lOH)-acridinedione(8uuu). To a suspension of 1.9 g (0.04 mol) of 50% sodium hydride in 15 mL of NJV-dimethylformamide at -10 OC was added dropwise a solution of 10.3 g (0.04 mol) of 5-(2,4-dichlorophenyl)-1,3-cyclohexanedione in 70 mL of NJVdimethylformamide. Frothing and a temperature rise to about 5 "C occurred. The resulting mixture was stirred at room temperature for 1h and then cooled to 5 OC. A solution of 7.9 g (0.04 mol) of 4-chloroisatoic anhydride in 60 mL of N,N-dimethylfonnamide was added in a stream. The resulting orange solution was heated to 90 OC for 4 h. It was poured into 2000 mL of ice-water containing 15 mL of concentrated hydrochloric acid. The off-white solid which separated was collected and washed with water. It was triturated in a mixture of 300 mL of ethanol and 200 mL of N,N-dimethylformamide on a steam bath for 40 min. The suspension was cooled to 5 "C, the solid was collected and rinsed consecutively with ethanol and then ether. Drying in vacuo at 90 "C for 6 h afforded 11.2 g (71%) of the title compound, mp >330 "C. An analytical sample was obtained by recrystallizing 2.4 g of the product from N,N-dimethylformamide-ethanol. Drying in vacuo at 90 "C for 6 h provided 2.1 g (88%recovery), mp 342-344 OC. Anal. (C1dl2Cl3NO2)C, H, N, C1. 8eee: XCORFE NMR (300 MHz, TFA-d) 6 1.32 (d, J = 5.6 Hz, 3), 3.2-3.4 (m, l),3.4-3.5 (m, l),3.6-4.0 (m, 2), 7.29 (d, J = 6.2 Hz, l),7.52 (8, l), 7.59 (d, J = 7.9 Hz, l), 8.07 (d, J = 8.4 Hz, l),8.20 (d, J = 6.7 Hz, l),8.67 ( 8 , 1). Compounds in Table I1 prepared similarly are designated Procedure F.
mL of ethanoL The resulting red solution was heated under reflux for 1.5 h and then allowed to cool to room temperature. The reaction mixture was concentrated to drynese in vacuo. The red solid residue was recrystallized from dichloromethane-ether. Drying in vacuo at 80 OC for 4 h afforded 4.1 g (95%) of the title compound, mp 194-195 OC. Anal. (CzsHzeClF3N302) C, H, N, C1, F. Compounds in Tables I11 and IV prepared similarly are designated procedure H.
Procedure J. 7-Chloro-l,3,4,10-tetrahydro-l0-hydroxy1-[ [2-(2-propenylamino)ethyl]imino]-3-[4-(trifluoromethyl)phenyl]-9(2H)-acridinone (3fff). To 3.3 g (0.008mol) of 7-chloro-3,4-dihydro-l0-hydroxy-3-[4-(trifluoromethyl)phenyl]-l,9(W,lOH)-acridinedione in 90mL of benzene was used a solution of 0.8 g (0.008mol) of N-2-propenyl-1,2-etediamine in 10 mL of benzene. The resulting red solution was heated under reflux for 2 h while water was removed with a Dean-Stark trap and then allowed to cool to room temperature. The reaction mixture was concentrated to dryneas in vacuo. The residual solid was recrystallized from ethyl acetata-ether. Drying in vacuo at 50 "C for 16 h afforded 3.1 g (78%) of the title compound, mp 116-119 "C. Anal. (C2bH23ClF3N302) C, H, N, C1, F. Compounds in Tables I11 prepared similarly are designated procedure J.
4-(Acetyloxy)-7-chloro-3,4-dihydro-3,3-dimethyl-l,9(2H,lOH)-acridinedione. A mixture of 4.0 g (0.014 mol) of 7-chloro-3,4-dihydro-l0-hydroxy-3,3-dimethyl-l,9(2H,lO~)acridinedione in 40 mL of acetic anhydride was heated on a steam bath for 1.45 h. The resulting solution was evaporated in vacuo,
Procedure G. 7-Chloro-3,4-dihydro-3,3-dimethyl-1,9- and the residue was recrystallized twice from cyclohexane and (2H,lOH)-acridinedione(8t). To a mixture of 25.0 g (0.086 mol) once from ethanol to give 1.7 g (36%)of product, mp 170 OC with of 7-chloro-3,4-dihydro-l0-hydroxy-3,4-dimethyl-1,9(W,10H)- resolidification, and melting again at 217-222 OC. Anal. (C1,-
acridinedione in 700 mL of methanol was added dropwise a solution of 4.9 g (0.086 mol) of sodium methoxide in 25 mL of methanol. To thia mixture was added a solution of 8.0 mL (0.086 mol) of iodomethane in 25 mL of methanol, and the mixture was heated under reflux for 1h. There was no evidence of a reaction, according to TLC, so an additional 40 mL of iodomethane was added, and the mixture was heated under reflux overnight. The initial suspension became a solution, and then a solid was deposited. This was removed by filtration and waehed with methanol to give 13.8 g (58%) of the product, mp >280 OC (lit.4 mp 300 "C). Anal. (C16H1&1N02), C, H, N. Addition of 4.9 g (0.086 mol) of sodium methoxide and 40 mL (0.65 mol) of iodomethane to the above filtrate and heating the solution under reflux overnight gave an additional 7.3 g of product; total yield 8970. This compound was originally synthesized3by deoxygenation with phosphorus trichloride. Procedure 1.3' 3,4-Dihydro-3,3dimethyl-L,9(2H,lOH)acridinedione (8tt). A solution of 5.6 g (0.04 mol) of 5,5-dimethylcyclohexane-l,3-dione,6.0 g (0.04 mol) of methylanthranilate, and 0.8 g (0.004 mol) of p-toluenesulfonic acid, monohydrate in 150 mL of toluene was heated under reflux with a Dean-Stark water separator for 5 h. At this time 5.9 g (0.044 mol) of zinc chloride was added and refluxing was continued for 24 h. The solvent was decanted, and the residual gum was triturated with several portions of water. Subsequent trituration with methanol-ether gradually induced crystallization. The solid was collected and suspended in 100 mL of N,N-dimethylformamide. The suspension was heated on a steam bath for 0.5 h, cooled to 0 OC and the solid collected. Drying in vacuo at 90 "C for 16 h afforded 1.7 g (18%over 2 steps) of the title compound, mp 347-348 OC. An analytical sample with no change in melting point was obtained by recrystallization from NJV-dimethylformamide-methanol. Recovery = 71%. Anal. (CI5Hl5NO2)C, H, N. Procedure H. 7-Chloro-1,3,4,10-tetrahydro-l0-hydroxy1-[ [3 4l-piperidinyl)propyl]imino]-3-[4 4 trifluoromethy1)phenyl]-9(2H)-acridinone(3yy). To 3.3 g (0.008 mol) of 7chlom-3,4-dihydro-l0-hydroxy-3[4-(trifluoromethyl)phenyl]1,9(W,lOH)-acridinedionein 140 mL of ethanol was added a solution of 1.1g (0.008mol) of 1-piperidinepropanamine in 10 (31) Sivaswami, T. S.; Iyer, B. M. Studies with Methone: Curr. Sci. (India) 1950, 19, 180.
Part I.
Hl&lNO,) C, H,N. The product was determined to be 4-(acetyloxy)-7-chlore-3,4dihydro-3,3-dimethyl-l,9(W,lOH)-acridinedioneand not the expected 10-(acetyloxy)-7-chloro-3,4-dihydro-3,3-dimethyl1,9(W,lOH)-acridinedione on the basis of its NMR spectrum. In CDCl3 with two drops of DMSO added, there were two, threeproton singleta at 1.1-1.2 6, assigned to the gem-dimethyl groups. There was also a three-proton singlet at 2.2 6 assigned to the acetyloxy group. A sharp tweproton doublet of doublets centered at 2.8 6 was assigned to the nonequivalent methylene protons. A one-proton singlet at 6.05 6 was assigned the methine proton. The three aromatic protons occurred as a multiplet at 7.6-8.3 6 and the nitrogen proton as a broad, exchangeable peak at 14 6. Of critical importance here was the one-proton singlet at 6.05 6, which excluded the 10-(acetyloxy)-acridinedionestructure.
44Acetyloxy)-7-chloro-3-( 3,4-dichlorophenyl)-3,4-dihydro-l,9(2H,lOH)-acridinedione(6). To a stirred mixture of 2.2 g (0.0054 mol) of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-lO-hydroxy-l,9(W,lOH)-acridinedionein 100 mL of dry benzene was added 0.42 mL (0.0059 mol) of acetyl chloride. The mixture was stirred at room temperature for 4 h, an additional 0.42 mL of acetyl chloride was added, and the mixture was stirred overnight. The mixture was evaporated in vacuo. The residue was triturated with 400 mL of hot ethanol and filtered to give 0.8 g of product. The cooled triturate gave a second crop of 0.6 g of product. The two crops were combined to give 1.4 g (58%) of product, mp 239-241 "C dec. Anal. (C21H14C13N04)C, H, N. The NMR (DMSO) spectrum showed two seta of doublets for the methine proton and two broad singleta for the nitrogen proton. This suggests the presence of geometric isomers.
l-(Acetyloxy)-7-chloro-3-(3,4-dichlorophenyl)-9( loa)acridinone (7). To a stirred, cooled mixture of 8.91 g (0.0218 mol) of 7-chlore3-(3,~dichlorophenyl)-3,4-dihydro-l0-hydro~y1,9(W,lOH)-acridinedionein 100 mL of pyridine was added dropwise, during 10 min, 12.4 mL (0.13 mol) of acetic anhydride. The resulting mixture was stirred at room temperature overnight and filtered to give 4.10 g of material. The solid was triturated in 200 mL of boiling ethanol to give 2.29 g (24.3%) of slightly impure product Upon cooling,the filtrate deposited a solid which was collected by filtration to give 0.79 g (8.4%) of product as a light yellow powder: mp 268-278 "C; NMR (90MHz, TFA-d) 6 = 2.3 (e, 3, CHJ, 7.4-8.7 (m, 8,ArH); MS m/e = 431 (M+);1R (KBr) Y 3320,1740,1636cn-'; IR (CHCld Y 3340,1740,1635,1610 cm-l. Anal. (Cz1Hl2Cl3NO3) C, H, N.
3446 Journal of Medicinal Chemistry, 1992, Vol. 35,No.19 7-Chloro-3,4-dihydro-3-[4-(trifluoromethy1)phenyll-1(tH)-acridinone (11). A mixture of 24.46 g (0.157 mol) of crude 2-amino-5-chlorobenzaldehydeand 16.68 g (0.0651 mol) of 5[4-(trifluoromethyl)phenyl]-1,3-cyclohexanedione in 200 mL of ethanol and 2.0 mL of piperidine was heated under reflux overnight. The resulting mixture was cooled and filtered to give 16.20 g of solid. Recrystallization from acetonitrile gave 12.24 g [50% based on 5- [4-(trifluoromethyl)phenyl] -1,3-cyclohexanedione] of the product as shiny, off-white crystals, mp 200-202 "C. Anal. (CmHl3C1F3NO)C, H, N. Since the possibility existed that the product was the following 1-phenyl structures,
g
a COSY32spectrum was obtained to identify protons directly coupled with each other. One of the five aliphatic resonances was coupled to all four remaining aliphatic resonances. Only structure 11 is consistent with this observation. NMR (300 MHz, MezSO-ds): 6 2.9-3.0 (m, l),3.1-3.3 (m, l), 3.3-3.5 (m, I), 3.5-3.7 (m, l),3.7-3.9 (m, I),7.66 (d, J = 8.1 Hz, 2), 7.74 (d, J = 8.4 Hz, 2), 7.89 (dd, J = 9.3, 2.3 Hz, l),8.03 (d, J = 9.0 Hz, l),8.36 (d, J = 2.2 Hz, l),8.94 ( 8 , 1).
N'-[ 7-Chloro-1,2,3,4-tetrahydro-3-[4-(trifluoromethyl)phenyl]-l-acridinylidene]-~,N-dimethyl-l,3-propanediamine. A solution of 2.00 g (0.00532 mol) of 7-chloro-3,4-dihydr0-3-[4-(trifluoromethyl)phenyl]-l(2H)-acridinone, 6.0 g (0.059 mol) of NJV-dimethyl-1,3-propanediamine, and a catalytic amount of 4toluenesulfonic acid, monohydrate in 100 mL of toluene was heated under reflux overnight. The solution was cooled and evaporated in vacuo to give a yellow solid. Two recrystallizations from acetonitrile gave 1.93 g (78.8%) of the product as a brilliant yellow solid, mp 146-148 "C. Anal. (C26H2sC1F3N3) C, H, N. 7-Chloro-3,4-dihydro-3-[4-(trifluoromethyl)phenyl]-1(2H)-acridinone, 10-Oxide. To a solution of 5.00 g (0.0133 mol) of 7-chloro-3,4-dihydro-3-[4-(trifluoromethyl)phenyl]-1(2H)acridinone in 125 mL of chloroform cooled in an ice bath was added dropwise during 1h a solution of 2.97 g (0.0146 mol) of 85% m-chloroperoxybenzoicacid in 75 mL of chloroform. The solution was allowed to stir a t room temperature overnight, an additional 1.50 g of m-chloroperoxybenzoic acid in 70 mL of chloroform was added to the reaction solution, and stirring was continued overnight. The reaction solution was extracted with a saturated sodium carbonate solution, washed with a saturated sodium chloride solution, dried (Na&304), and evaporated in vacuo to give 5.22 g of a yellow solid. The solid was triturated in 300 mL of boiling ethanol to give 3.53 g of impure product. Another 0.58 g of product was collected from the cooled triturate (crude yield 79%). Recrystallization of 1.90 g of material gave 1.48 g (78'70 recovery) of the product as a dull yellow solid, mp 238 "C dec. Anal. (CzoHl3C1F3NOz) C, H, N. 5-Chloro-2-[[5-[ 4-(trifluoromethyl)phenyl]-3-oxo-l-cyclohexenyl]amino]benzonitrile. A mixture of 15.26 g (0.01 mol) of 2-amino-5-chlorobenzonitrile, 25.62 g (0.10 mol) of 5-[4-(trifluoromethyl)phenyl]-1,3-cyclohexanedione,and 1.00 g of 4toluenesdfonic acid monohydratein 750 mL of toluene was heated under reflux with a Dean-Stark trap for 8 h. The resulting solution was cooled and filtered to give 36.04 g (90.58%) of product as a cream solid, mp 246 "C dec. Anal. (C2,H1,C1F3N2O)C, H, N. 9-Amino-7-chloro-3,4-dihydro-3-[ 4 4trifluoromethy1)phenyl]-1(2H)-acridinone (12). A mixture of 36.0 g (0.0921 mol) of 5-chloro-2-[ [5-[4-(trifluoromethyl)phenyl]-3-oxo-l-cyclohexenyl]amino]benzonitrile and 1.00 g (0.00734 mol) of zinc chloride in 1.5 L of xylene was heated under reflux with a Dean-Stark trap for 3 h. The mixture was filtered hot and the (32) Bax, A. D.; Freeman, R.; Morris, G. A. J.Magn. Reson. 1981, 42, 169.
Kesten et al. Scheme VI HN - C y
ti small amount of solid collected was discarded. The filtrate was cooled and filtered to give 27.89 g (77.5%) of product as a dark cream solid, mp 265 OC dec. Anal. (CmH&1F3N20) C, H, N. Since the possibility existed that the product was the 1-phenyl analog shown,
a COSY spectrum was obtained. One of the five aliphatic resonances was coupled to all remaining four aliphatic reaonancea and only structure 12 with its 3-hydrogen adjacent to the other four aliphatic protons is consistent with this observation. The COSY spectrum also a d d r d the tautomeric form of the product. The two hydrogens on nitrogens were observed to be coupled to one another providing evidence that the material exists in the amino tautomeric form depided NMR (300 MHz, MegO-dJ 6 2.7-2.9 (m, l),3.0-3.1 (m, l),3.1-3.2 (m, l),3.3-3.4 (m, 11, 3.5-3.7 (m, l),7.63 (d, J = 8.4 Hz, 2), 7.7-7.8 (m, 4), 8.54 (8, l),8.58 (br s, exchangeable), 10.02 (br I, exchangeable).
7-Chloro-3,4-dihydro-9-(methylamino)-3-[4-(trifluoromethyl)phenyl]-1(2H)-acridinone. To a mixture of 2.0 g (0.005 72 mol) of 9-amino-7-chloro-3,4-dihydro-3-[4-(trifluoromethyl)phenyl]-1(2H)-acridinone in 30 mL of NJV-dimethylformamide was added a mixture of 0.14 g (0.0056 mol) of sodium hydride (from0.28 g of 50% suspension in oil washed with hexane) in 5 mL of NJV-dimethylformamide. The resulting dark brown solution was stirred at room temperature for 15 min and treated with a solution of 0.79 g (0.0056 mol) of iodomethane in 10 mL of NJV-dimethylformamide. After 1 h another 0.40 g of iodomethane was added. After 1 h a mixture of 0.05 g of sodium hydride (from 0.10 g of 50% suspension in oil washed with hexane) in 3 mL of NJV-dimethylformamide, followed by a solution of 0.40 g of iodomethane in 5 mL of NJV-dimethylformamide was added to the reaction solution. The solution was stirred at room temperature overnight, diluted with ice-water, and filtered. The collected solid was recrystallized twice from acetonitrile to give 0.50 g (24%) of product as a shiny, gold solid, mp 224-226 "C. Anal. (C21H1BC1F3N20) C, H, N. The NMR of the product confirmed that methylation had occurred on the %amino group and not the ring nitrogen (see Scheme VI). The methyl group absorbed as a doublet, being split by the hydrogen on the nitrogen, which coalesced to a singlet upon the addition of DzO: NMR (90 MHz, CDC13) 6 2.8-3.4 (m, 51, 3.5 (d, J = 6 Hz,3, coalesces to singlet upon D20 addition), 7.3-7.8 (m, 6), 8.3 (d, J = 2 Hz, l),9.5 (br, 1, exchangeable). 7,9-Dichloro-3,4-dihydro-3-[ 4-(trifluoromethy1)phenylll(2H)-acridinone. A mixture of 10.0 g (0.0255 mol) of 7chloro-3,4-dihydro-3-[4-(trifluoromethyl)phenyl]-1,9(W,lOH)acridinedioneand 250 mL of phosphorus oxychloride was heated under reflux for 1h. The resulting black solution was cooled and evaporated in vacuo to give a black solid. The solid was dissolved
7-Chloro-3-substituted-3,4-dihydro-1,9(2H,lO~-acridinediones Journal of Medicinal Chemistry, 1992, Vol. 35, No.19 3447 in chloroform and dropped into a vigorously stirred, ice cold, dilute sodium hydrogen carbonate solution. The layers were separated, and the chloroform solution was washed with dilute sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride. The solution was filtered through Celite, dried (MgSO,), and evaporated in vacuo to give 8.62 g of a black solid. Chromatography over 500 g of silica gel with chloroform as the eluent gave 1.29 g (12.3%) of the product as a gray solid, mp 161-163 'C. Anal. ( C a & & F a O ) H, N C dd,58.55;found, 58.03.
showed no free NH stretch, which suggests the compound exists in the intramolecularly hydrogen bonded form:
7-Chloro-9-[[3-(dimethylamino)propyl]amino]-3,4-dihydro-3-[ rl-(trifluoromet hyl)phenyl]- 1(2H)-acridinone. A mixture of 1.3 g (0.0032mol) of 7,9-dichloro-3,4-dihydro-3-[4(trifluoromethyl)phenyl]-l(2H)-acridinone and 0.36 g (0.0035mol) of NJV-dimethyl-113-propanediamine in 100 mL of ethanol was heated under reflux for 3 h. To the solution was added another 3.2 g of NJV-dimethyl-1,3-propan~~inel and the solution was heated under reflux for 30 min. The solution was cooled and filtered to give a solid. Recrystallization from acetonitrile gave 0.75 g (50%) of the product as a pale yellow solid, mp 147-149 OC. Anal. (C&&lF,N,O) H,N; C: d c d , 63.09,found, 62.53. An infrared spectrum of the compound in a chloroform solution
Acknowledgment. We thank Dr.F. M. MacKellar and associates for the microanalytical and spectral data and Drs. M.Musallam and R. Engle of the Walter Reed A r m y Institute of Research for biological data. Supplementary Material Available: Contour plots of the XCORFE spectra of 8y and 8888 and the COSY spectra of 11 and 12 (5pages). Ordering information is given on any current masthead page.
